Urinary incontinence is the involuntary discharge of urine. This occurs in an uncontrolled manner when the pressure within the urinary bladder exceeds the pressure needed to close the ureter. Causes can be, on the one hand, an increased internal pressure in the bladder (e.g., due to detrusor instability) with the consequence of urgency incontinence, and, on the other, a reduced sphincter pressure (e.g., following giving birth or surgical interventions) with the consequence of stress incontinence. The detrusor is the coarsely bundled multilayered bladder wall musculature, contraction of which leads to voiding of urine, and the sphincter is the closing muscle of the urethra. Mixed forms of these types of incontinence and so-called overflow incontinence or reflex incontinence (e.g., following damage to the spinal cord) occur. Thus, for example, urinary incontinence, an urge to urinate and an increased frequency of micturition are all possible symptoms of benign prostate hyperplasia. Further details of this complex are to be found in Chutka, D. S, and Takahashi, P. Y., 1998, Drugs 560: 587-595.
The urge to urinate is the state, aimed at voiding of urine (micturition), of increased bladder muscle tension as the bladder capacity is approached (or exceeded). This tension acts here as a stimulus to micturition. An increased urge to urinate is understood here in particular as the occurrence of premature or an increased and sometimes even painful urge to urinate up to so-called strangury. This consequently leads to a significantly more frequent micturition. Causes can be, inter alia, inflammations of the urinary bladder and neurogenic bladder disorders, and also bladder tuberculosis. However, not all the causes have yet been clarified.
An increased urge to urinate and also urinary incontinence are perceived as extremely unpleasant and there is a clear need among persons affected by these indications to achieve an improvement which is as long-term as possible.
An increased urge to urinate and in particular urinary incontinence are conventionally treated with medicaments using substances which are involved in the reflexes of the lower urinary tract (Wein, A. J., 1998, Urology 51 (Suppl. 21): 43-47). These are usually medicaments which have an inhibiting action on the detrusor muscle, which is responsible for the internal pressure in the bladder. These medicaments are, e.g., parasympatholytics, such as oxybutynin, propiverine or tolterodine, tricyclic antidepressants, such as imipramine, or muscle relaxants, such as flavoxate. Other medicaments, which in particular increase the resistance of the urethra or of the neck of the bladder, show affinities for α-adrenoreceptors, such as ephedrine, for β-adrenoreceptors, such as clenbutarol, or are hormones, such as oestradiol.
The review article by K. E. Andersson et al. “The pharmacological treatment of urinary incontinence”, BJU International (1999), 84, 923-947 gives an accurate insight here into the therapeutics and treatment methods used, in particular in respect of anti-muscarine agents and other substances having a peripheral action.
Certain diarylmethylpiperazines and -piperidines are also described for this indication in WO 93/15062. For tramadol also a positive effect on bladder function has been demonstrated in a rat model of rhythmic bladder contractions (Nippon-Shinyaku, WO 98/46216). There are furthermore investigations for characterization of the opioid side effect of urinary retention in the literature, from which some indications of the influencing of bladder functions by weak opioids, such as diphenoxylate (Fowler et al., 1987 J. Urol 138:735-738) and meperidine (Doyle and Briscoe, 1976 Br J Urol 48:329-335), by mixed opioid agonists/antagonists, such as buprenorphine (Malinovsky et al., 1998 Anesth Analg 87:456-461; Drenger and Magora, 1989 Anesth Analg 69:348-353), pentazocine (Shimizu et al. (2000) Br. J. Pharmacol. 131 (3): 610-616) and nalbuphine (Malinovsky et al., 1998, loc. cit.), and by potent opioids, such as morphine ((Malinovsky et al., 1998 loc. cit.; Kontani and Kawabata, (1988); Jpn J. Pharmacol. September; 48(1):31) and fentanyl (Malinovsky et al., 1998 loc. cit.) result. Nevertheless, these investigations were usually carried out in analgesically active concentrations.
In the case of the indications in question here, it should be remembered that it is in general a matter of very long-term uses of medicaments and, in contrast to many situations where analgesics are employed, those affected are faced with a situation which is very unpleasant but not intolerable. It is therefore to be ensured here—even more so than with analgesics—that side effects are avoided if the person affected does not want to exchange one evil for another. Also, analgesic actions are also largely undesirable during permanent treatment of urinary incontinence.